Immunosuppressive agent leflunomide: a SWNTs-immobilized dihydroortate dehydrogenase inhibitory effect and computational study of its adsorption properties on zigzag single walled (6,0) carbon and boron nitride nanotubes as controlled drug delivery devices.

Abstract

Leflunomide [HWA 486 or RS-34821, 5-methyl-N-(4trifluoromethylphenyl)-4-isoxazole carboximide] is an immunosuppressive agent effective in the treatment of rheumatoid arthritis. Dihydroortate dehydrogenase (DHODH, EC 1.3.3.1) immobilization on the nanotubes was carried out and biochemical characterization of free and immobilized enzyme was determined. In comparison with free enzyme, the immobilized DHODH showed improved stability and reusability for investigation of inhibition pattern of drugs such as leflunomide. The experimental data showed that, DHODH was inhibited by the active metabolite of leflunomide (RS-61980) with a Ki and KI of 0.82 and 0.06 mM, respectively. Results exhibited mixed-type inhibition kinetics towards dihydroorotate as a substrate in the free and immobilized enzyme. Furthermore, the behavior of anticancer drug leflunomide adsorbed on the external surface of zigzag single walled (6,0) carbon and boron nitride nanotubes (SWCNT and SWBNNT) was studied by means of DFT calculations at the B3LYP/6-31G(*) level of theory. The larger adsorption energies and charges transfer showed that the adsorption of leflunomide onto SWBNNT is more stable than that the adsorption of leflunomide onto SWCNT. Frontier molecular orbitals (HOMO and LUMO) suggest that adsorption of leflunomide onto SWBNNT behave as charge transfer compounds with leflunomide as an electron donor and SWBNNT as an electron acceptor. Thus, nanotubes (NTs) have been proposed and actively explored as multipurpose innovative carriers for drug delivery and diagnostic application. The AIM theory has been also applied to analyze the properties of the bond critical points: their electron densities and their laplacians. Also, the natural bond orbital (NBO) calculations were performed to derive natural atomic orbital occupancies, and partial charges of the interacting atoms in the equilibrium tube-molecule distance.

• Authors: Heidar Raissi, Fariba Mollania
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 56 Pg. 37-54 (Jun 2 2014) ISSN: 1879-0720 [Electronic] Netherlands
• PMID: 24566615 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Boron Compounds
• Enzymes, Immobilized
• Immunosuppressive Agents
• Isoxazoles
• boron nitride
• Carbon
• Oxidoreductases Acting on CH-CH Group Donors
• dihydroorotate dehydrogenase
• leflunomide

Topics

• Adsorption
• Boron Compounds
• Carbon
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Delivery Systems
• Enzymes, Immobilized (antagonists & inhibitors, chemistry)
• Humans
• Immunosuppressive Agents (pharmacology)
• Isoxazoles (pharmacology)
• Nanotubes (chemistry)
• Oxidoreductases Acting on CH-CH Group Donors (antagonists & inhibitors, chemistry)